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Interaction of infectious spleen and kidney necrosis virus ORF119L with PINCH
leads to dominant-negative inhibition of integrin-linked kinase and
cardiovascular defects in zebrafish
#MMPMID25355883
Yuan JM
; He BL
; Yang LY
; Guo CJ
; Weng SP
; Li SC
; He JG
J Virol
2015[Jan]; 89
(1
): 763-75
PMID25355883
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Infectious spleen and kidney necrosis virus (ISKNV) is the type species of the
Megalocytivirus genus, Iridoviridae family, causing a severe systemic disease
with high mortality in mandarin fish (Siniperca chuatsi) in China and Southeast
Asia. At present, the pathogenesis of ISKNV infection is still not fully
understood. Based on a genome-wide bioinformatics analysis of ISKNV-encoded
proteins, we found that ISKNV open reading frame 119L (ORF119L) is predicted to
encode a three-ankyrin-repeat (3ANK)-domain-containing protein, which shows high
similarity to the dominant negative form of integrin-linked kinase (ILK); i.e.,
viral ORF119L lacks the ILK kinase domain. Thus, we speculated that viral ORF119L
might affect the host ILK complex. Here, we demonstrated that viral ORF119L
directly interacts with particularly interesting Cys-His-rich protein (PINCH) and
affects the host ILK-PINCH interaction in vitro in fathead minnow (FHM) cells. In
vivo ORF119L overexpression in zebrafish (Danio rerio) embryos resulted in
myocardial dysfunctions with disintegration of the sarcomeric Z disk.
Importantly, ORF119L overexpression in zebrafish highly resembles the phenotype
of endogenous ILK inhibition, either by overexpressing a dominant negative form
of ILK or by injecting an ILK antisense morpholino oligonucleotide. Intriguingly,
ISKNV-infected mandarin fish develop disorganized sarcomeric Z disks in
cardiomyocytes. Furthermore, phosphorylation of AKT, a downstream effector of
ILK, was remarkably decreased in ORF119L-overexpressing zebrafish embryos. With
these results, we show that ISKNV ORF119L acts as a domain-negative inhibitor of
the host ILK, providing a novel mechanism for the megalocytivirus pathogenesis.
IMPORTANCE: Our work is the first to show the role of a dominant negative
inhibitor of the host ILK from ISKNV (an iridovirus). Mechanistically, the viral
ORF119L directly binds to the host PINCH, attenuates the host PINCH-ILK
interaction, and thus impairs ILK signaling. Intriguingly, ORF119L-overexpressing
zebrafish embryos and ISKNV-infected mandarin fish develop similar disordered
sarcomeric Z disks in cardiomyocytes. These findings provide a novel mechanism
for megalocytivirus pathogenesis.
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